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Rescuing Anti-tumor Responses of TCR-Td T Cells by NKG2D-stimulation

通过 NKG2D 刺激挽救 TCR-Td T 细胞的抗肿瘤反应

基本信息

批准号：
9313795
负责人：
Jose Alejandro Guevara-Patino
金额：
$ 31.33万
依托单位：
LOYOLA UNIVERSITY CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-08 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9313795
关键词：
Adoptive Cell Transfers Agonist Antibodies CD8-Positive T-Lymphocytes Cancer Patient Cell Differentiation process Cell Line Clinical Clinical Research Clinical Trials Cues Data Distal Effectiveness Environment Genes Genetic Transcription HLA-A2 Antigen Human Immune Immunosuppression Individual MAPK8 gene Malignant Neoplasms Mediating Mediator of activation protein Melanoma Cell Modeling Mus PDPK1 gene Pathway interactions Pharmacology Phosphotransferases RGS3 gene Reporting Resistance Role Signal Pathway Signal Transduction System T-Cell Receptor T-Lymphocyte Testing Therapeutic Time Transgenic Mice Tumor Antigens Tumor Immunity Up-Regulation Work cellular transduction experimental study genetically modified cells improved in vivo inhibitor/antagonist knock-down melanoma mutant novel overexpression protein expression public health relevance receptor response treatment response tumor tumor growth tyrosinase peptide

项目摘要

DESCRIPTION (provided by applicant): Adoptive cell transfer of T cells genetically modified to express a T cell receptor reactive to a tumor antigen (TCR-Td T cells) has emerged as one of the most promising approaches for the treatment of malignancies. However, recent clinical studies report objective clinical response rates lower than 30%. Providing a plausible explanation for these responses, studies have shown that, in tumor-bearing hosts, transferred T cells encounter an inhospitable environment characterized by immune suppression. Hence, rendering TCR-Td CD8+ T cells resistant to these negative environmental cues could significantly improve clinical responses in cancer patients. Given the stimulatory role of the NKG2D receptor, we investigated its ability to control CD8+ T cell suppression. Our data show for the first time that NKG2D stimulation in human TCR-Td CD8+ T cells (similar to those used in clinical trials) and mouse CD8+ T cells results in complete resistance to suppression by TGF-� and augmented therapeutic anti-tumor responses against melanoma. Our data also show that NKG2D-activated TCR-Td CD8+ T cell resistance to suppression by TGF-� is accompanied by the upregulation of two negative regulators of TGF-� signaling, RGS3 and PDPK1. While these findings depict novel functions for NKG2D in CD8+ T cells, how these pathways are interconnected in NKG2D signaling and resistance to suppression remains to be determined. We hypothesize that NKG2D-induced resistance of TCR-Td CD8+ T cells to suppression is mediated by the PI3K, Grb2, and JNK pathways and the combined effects of RGS3 and PDPK1. Thus, the objective of this proposal is to dissect the proximal and distal signaling pathways utilized by NKG2D to confer resistance to TGF-� and enhanced anti-tumor immunity. To do this, we will use human and mouse CD8+ T cells transduced to express a TCR against a tyrosinase peptide/HLA-A2 and h3T transgenic mice, which express the same receptor. Our study posits a new paradigm; human CD8+ T cells can be transcriptionally manipulated by NKG2D signaling to achieve resistance to TGF-�. We believe that human TCR-Td CD8+ T cells could be easily conditioned prior to ACT by an NKG2D agonist to enhance their survival and therapeutic anti-tumor capacity.

描述（由申请人提供）：经遗传修饰以表达对肿瘤抗原具有反应性的T细胞受体的T细胞（TCR-Td T细胞）的连续细胞转移已成为治疗恶性肿瘤的最有希望的方法之一。然而，最近的临床研究报告客观临床反应率低于30%。为这些反应提供了一个合理的解释，研究表明，在荷瘤宿主中，转移的T细胞遇到了一个以免疫抑制为特征的不适宜环境。因此，使TCR-Td CD 8 + T细胞对这些负面环境线索具有抗性可以显著改善癌症患者的临床反应。鉴于NKG 2D受体的刺激作用，我们研究了其控制CD 8 + T细胞抑制的能力。我们的数据首次表明，NKG 2D刺激人TCR-Td CD 8 + T细胞（类似于临床试验中使用的那些）和小鼠CD 8 + T细胞导致对TGF-β抑制的完全抵抗，并增强了对黑色素瘤的治疗性抗肿瘤反应。我们的数据还表明，NKG 2D激活的TCR-Td CD 8 + T细胞对TGF-β抑制的抵抗伴随着TGF-β信号传导的两个负调节因子RGS 3和PDPK 1的上调。虽然这些发现描述了NKG 2D在CD 8 + T细胞中的新功能，但这些途径如何在NKG 2D信号传导和抑制抗性中相互关联仍有待确定。我们假设NKG 2D诱导的TCR-Td CD 8 + T细胞对抑制的抗性是由PI 3 K、Grb 2和JNK通路以及RGS 3和PDPK 1的联合作用介导的。因此，本提案的目的是剖析NKG 2D利用的近端和远端信号通路，以赋予对TGF-β的抗性和增强的抗肿瘤免疫力。为此，我们将使用转导以表达针对酪氨酸酶肽/HLA-A2和h3 T转基因小鼠的TCR的人和小鼠CD 8 + T细胞，其表达相同的受体。我们的研究提出了一个新的范例;人CD 8 + T细胞可以通过NKG 2D信号转导进行转录操纵，以实现对TGF-β的抗性。我们认为，人TCR-Td CD 8 + T细胞可以在ACT之前通过NKG 2D激动剂容易地调节，以提高其存活率和治疗性抗肿瘤能力。